This study was designed to investigate the potential for targeting the NF-kB inducing kinase, NIK, in two common B-cell malignancies, chronic lymphocytic leukemia (CLL) and multiple myeloma (MM). Using a selective NIK inhibitor, CW15337, we were able to demonstrate that cell lines and primary tumor cells were sensitive to the effects of NIK inhibition, whilst normal lymphocytes were significantly more resistant to its cytotoxic effects. Sensitivity to CW15337 was associated with the nuclear expression of the NF-kB subunit, p52. Importantly, tumor samples from a subset of poor prognosis CLL patients, with mutations in a gene called BIRC3, showed elevated p52 expression and were particularly sensitive to NIK inhibition. Furthermore, the combination of CW15337 and ABT-199 (venetoclax) reversed the drug resistance observed when treating tumor cells with ABT-199 alone. Our study shows the potential for targeting NIK in both CLL and MM.